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In Silico Screening-Based Discovery of Novel Inhibitors of Human Cyclic GMP-AMP Synthase: A Cross-Validation Study of Molecular Docking and Experimental Testing

文献类型：期刊论文

作者Zhao, Wenfeng2,3,4; Xiong, Muya1,4; Yuan, Xiaojing1,4; Li, Minjun5; Sun, Hongbin2,3; Xu, Yechun1,4
刊名JOURNAL OF CHEMICAL INFORMATION AND MODELING
出版日期2020-06-22
卷号60期号:6页码:3265-3276
ISSN号1549-9596
DOI10.1021/acs.jcim.0c00171
通讯作者Sun, Hongbin(hongbinsun@cpu.edu.cn) ; Xu, Yechun(ycxu@simm.ac.cn)
英文摘要Cyclic GMP-AMP synthase (cGAS) has been recently uncovered to be a promising therapeutic target for immune-associated diseases. Until now, only a few inhibitors have been identified through high-throughput screening campaigns. Here, we reported the discovery of novel inhibitors for the catalytic domain of human cGAS (h-cGAS(CD)) by virtual screening for the first time. To generate a reliable docking mode, we first obtained a high-resolution crystal structure of h-cGAS(CD) in complex with PF-06928215, a known inhibitor of h-cGAS, followed by molecular dynamics simulations on this complex structure. Four fragment hits were identified by the virtual screening together with a thermal shift assay. The crystal structures of these four compounds in complex with h-cGAS(CD) were subsequently determined, and the binding modes of the compounds were similar to those predicted by molecular docking, supporting the reliability of the docking model. In addition, an enzyme activity assay identified compound 18 (IC50 = 29.88 +/- 3.20 mu M) from the compounds predicted by the virtual screening. A similarity search of compound 18 followed by a second virtual screening led to the discovery of compounds S2 (IC50 = 13.1 +/- 0.09 mu M) and S3 (IC50 = 4.9 +/- 0.26 mu M) as h-cGAS inhibitors with improved potency. Therefore, the present study not only provides the validated hit compounds for further development of h-cGAS inhibitors but also demonstrates a cross-validation study of virtual screening, in vitro experimental assays, and crystal structure determination.
WOS关键词AICARDI-GOUTIERES-SYNDROME ; DNA SENSOR ; CGAS ; PROTEIN ; 2ND-MESSENGER ; MODEL ; DINUCLEOTIDE ; INFLAMMATION ; PARAMETERS ; MUTATIONS
资助项目National Key R&D Program of China[2017YFB0202604] ; National Natural Science Foundation of China[21877122]
WOS研究方向Pharmacology & Pharmacy ; Chemistry ; Computer Science
语种英语
WOS记录号WOS:000543717300054
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/291980]  
专题中国科学院上海药物研究所
通讯作者Sun, Hongbin; Xu, Yechun
作者单位1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
2.China Pharmaceut Univ, Jiangsu Key Lab Drug Discovery Metab Dis, Nanjing 210009, Peoples R China
3.China Pharmaceut Univ, State Key Lab Nat Med, Nanjing 210009, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
5.Chinese Acad Sci, Shanghai Adv Res Inst, Shanghai Synchrotron Radiat Facil, Shanghai 201210, Peoples R China
推荐引用方式
GB/T 7714		 Zhao, Wenfeng,Xiong, Muya,Yuan, Xiaojing,et al. In Silico Screening-Based Discovery of Novel Inhibitors of Human Cyclic GMP-AMP Synthase: A Cross-Validation Study of Molecular Docking and Experimental Testing[J]. JOURNAL OF CHEMICAL INFORMATION AND MODELING,2020,60(6):3265-3276.
APA Zhao, Wenfeng,Xiong, Muya,Yuan, Xiaojing,Li, Minjun,Sun, Hongbin,&Xu, Yechun.(2020).In Silico Screening-Based Discovery of Novel Inhibitors of Human Cyclic GMP-AMP Synthase: A Cross-Validation Study of Molecular Docking and Experimental Testing.JOURNAL OF CHEMICAL INFORMATION AND MODELING,60(6),3265-3276.
MLA Zhao, Wenfeng,et al."In Silico Screening-Based Discovery of Novel Inhibitors of Human Cyclic GMP-AMP Synthase: A Cross-Validation Study of Molecular Docking and Experimental Testing".JOURNAL OF CHEMICAL INFORMATION AND MODELING 60.6(2020):3265-3276.

入库方式： OAI收割

来源：上海药物研究所

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